HIV transmission risk behaviors are common and recalcitrant among persons with methamphetamine (METH) dependence, but their underlying cognitive and neurobiological mechanisms are not well understood. During the previous funding period we learned that METH dependence may differentially impact the expression of inhibitory deficits related to risk taking in the setting of HIV infection in humans and mouse models. Building on this work, the current application requests support for parallel human and animal research to determine the individual and combined effects of METH dependence, HIV infection and aging on risk taking. We will leverage our expertise in implementing cross-species measures by evaluating several important components of risk taking that will be isolated paradigmatically in humans and two mouse models of HIV: 1) Preference for risk, reward and/or novelty versus punishment avoidance, 2) motivation defined as willingness to work for a reward, and 3) inhibition. In the human study, we will test our hypothesis HIV and METH have differentiable effects on the multiple components that underlie risk taking in all 320 well-characterized subjects from the TMARC cohort that will be stratified by METH dependence, HIV serostatus, and age. We will also examine the impact of aging on the expression of risk behaviors in HIV and METH, as well as the unique effects of risk taking and its components on real-world outcomes (e.g., adherence) in our clinical groups. Shared human subjects with TMARC Project 2 will allow us to examine the neural substrates of risky decision-making, including neuroimaging indices of functional connectivity and white matter injury. The animal studies will employ two mouse models of HIV (i.e., constitutive gp120tg and conditional iTat-tg) with and without METH treatment that will be evaluated with cognitive paradigms that map directly on to those used with our human subjects. Collaborations with the TMARC Neuroimaging and Neuroscience and Animal Models Cores will us to parse out biological mechanisms of these critical cognitive functions in mouse models. The ultimate goal of this research is to propel the design prevention efforts that target specific components of risk taking in order to reduce HIV transmission.